亚胺培南在临床前中空纤维模型中的药代动力学/药效学、虚拟患者的剂量确定以及脓肿分枝杆菌肺病疗效的临床证据

Imipenem Pharmacokinetics/Pharmacodynamics in Preclinical Hollow Fiber Model, Dose Finding in Virtual Patients, and Clinical Evidence of Efficacy for Mycobacterium abscessus Lung Disease.

作者信息

Singh Sanjay, Gumbo Tawanda, Wang Jann-Yuan, Boorgula Gunavanthi D, Burke Andrew, Huang Hung-Ling, McShane Pamela J, Amaro-Galvez Rodolfo, Gross Jane E, Aryal Santosh, Heysell Scott K, Srivastava Shashikant

机构信息

Division of Infectious Diseases, Department of Medicine, School of Medicine, University of Texas at Tyler, Tyler, Texas, USA.

Mathematical Modeling and AI Department, Praedicare, Dallas, Texas, USA.

出版信息

J Infect Dis. 2025 Jul 11;231(6):1521-1531. doi: 10.1093/infdis/jiae601.

DOI:10.1093/infdis/jiae601

PMID:39688388

Abstract

BACKGROUND

Guideline-based therapy (GBT) for Mycobacterium abscessus (Mab) lung disease achieves sputum culture conversion (SCC) rates of 35%. This poor GBT efficacy is mirrored in the hollow fiber system model of Mab (HFS-Mab). While imipenem is part of GBT, its biologic effect, with or without β-lactamase inhibitors, is unproven.

METHODS

We performed imipenem-relebactam minimum inhibitory concentration (MIC) in 122 Mab isolates, and an exposure-response study in the HFS-Mab using human intrapulmonary pharmacokinetics. The percentage of time that concentration persisted above the MIC (TMIC), mediating maximal effect in the HFS-Mab, was used as the exposure target for dose finding in a Monte Carlo experiment including 10 000 virtual patients. For real-world evidence, we performed a patient, intervention (imipenem), comparison (no β-lactam), and outcome (SCC) (PICO) analysis.

RESULTS

Imipenem killed 1.32 log10 colony-forming units/mL below the day 0 level in HFS-Mab. The average target exposure for imipenem was a TMIC of 47.9% (SD, 9.77%). Infusion of 1 g every 6 hours achieved the target in >90% of virtual patients in Monte Carlo experiments. The pharmacokinetic-pharmacodynamic MIC break point was 1 mg/L. In PICO analyses, the median time to SCC was 470 days in comparators, 311 days for imipenem added on to a failing regimen, and 37 days in newly treated patients (P = .049). The odds ratio for SCC when imipenem was part of the initial regimen, versus comparators, was 12.5 (95% confidence interval, 1.47--84.55). No patients receiving imipenem experienced treatment-limiting adverse events, compared with 2 of 7 comparators (P = .046). Middlebrook 7H9 broth MIC distribution, read at 24 hours, was better correlated with patient responses than cation-adjusted Mueller-Hinton broth.

CONCLUSIONS

Imipenem demonstrated biologic effect in the HFS-Mab and in patients. Imipenem-relebactam doses of 1 g every 6 hours are recommended.

摘要

背景

播散型鸟分枝杆菌（Mab）肺病的基于指南的治疗（GBT）实现痰培养转阴（SCC）率为35%。这种GBT疗效不佳在Mab中空纤维系统模型（HFS-Mab）中也有体现。虽然亚胺培南是GBT的一部分，但其生物学效应，无论有无β-内酰胺酶抑制剂，都未经证实。

方法

我们对122株Mab分离株进行了亚胺培南-瑞来巴坦最低抑菌浓度（MIC）检测，并使用人体肺内药代动力学在HFS-Mab中进行了暴露-反应研究。浓度持续高于MIC的时间百分比（TMIC），介导HFS-Mab中的最大效应，被用作在包括10000名虚拟患者的蒙特卡洛实验中进行剂量探索的暴露目标。为了获得真实世界证据，我们进行了患者、干预（亚胺培南）、对照（无β-内酰胺类）和结局（SCC）（PICO）分析。

结果

亚胺培南在HFS-Mab中使菌落形成单位/mL比第0天水平降低1.32 log10。亚胺培南的平均目标暴露是TMIC为47.9%（标准差，9.77%）。每6小时输注1 g在蒙特卡洛实验中使>90%的虚拟患者达到目标。药代动力学-药效学MIC折点为1 mg/L。在PICO分析中，对照的SCC中位时间为470天，在失败方案中加用亚胺培南为311天，新治疗患者为37天（P = 0.049）。亚胺培南作为初始方案一部分时SCC的比值比相对于对照为12.5（95%置信区间，1.47 - 84.55）。与7名对照中的2名相比，接受亚胺培南治疗的患者均未出现限制治疗的不良事件（P = 0.046）。在24小时读取的Middlebrook 7H9肉汤MIC分布与患者反应的相关性优于阳离子调整的Mueller-Hinton肉汤。